This document summarizes research on treating eating disorders and obesity. It discusses: 1) Common treatments like CBT and behavioral therapy that have shown success in reducing binge eating but not leading to weight loss. Alternative therapies have also not resulted in weight loss. 2) Stress and brain regions involved in motivation, reward, and homeostatic regulation are implicated in overeating and weight gain. Studies show higher stress and activity in food reward regions in obese individuals. 3) Research exploring how hormones, metabolism, and brain responses to food cues are altered by factors like stress, hunger, and food consumption. Understanding these mechanisms may help develop new treatment approaches.

1. Treating Eating Dysfunction:
Understanding Mechanisms to Improve Treatments
Rajita Sinha, Ph.D.
Yale University School of Medicine

2.  Binge Eating Disorder
(insufficient restraint, chaotic eating & binge eat)
-- strongly associated with obesity
 Obesity (excessive energy intake with lower energy expenditure)

3. • CBT and BT – well established , and considered the
treatment of choice (50% remit but no weight loss)
• Alternative therapies (IPT, DBT, BWL) have support (but no
weight loss)
• CBT superior to pharmacotherapy
• Marked disconnect between big reductions in binge eating
and minimal weight change
(nice.org.uk; Reas & Grilo, Obesity 2008; Wilson, Grilo, & Vitousek, Am Psychol 2007)

5.  An event or series of events that are overwhelming,
traumatic or non-traumatic, challenging or threatening -
physical, social, emotional, cognitive or physiological in
nature.
 Multi-modal brain-mind-body responses; under prolonged
and repeated conditions, detrimental health effects:
– Unpredictable Stress > Predictable Stress
– More Intense > Less Intense Stress
– Prolonged Stress >Acute Stress
– High Repeated Stress > FewAdverse Events

6. Total Stress
By BMI
Normal Overweight Obese
MeanTotalStressScore
18
20
22
24
26
28
Normal BMI: 18 – 24.9
Overweight: 25 – 29.9
Obese: 30 and greater
N=588
X2
= 25.47, df=1, P < 0.0001
Odds ratio =1.146 (1.087-1.208)

7. “…All you can think about is having that cheesecake.Your
mouth waters.You can’t wait to taste that white creamy
sweet bite of heaven!… Your heart beats faster… Your
eyes scan the creamy cheesecake.Your mouth is watering…
You cut a huge piece!… It all looks so good.You can’t
wait to taste the sweet creamy texture and soft buttery
crust…You cut a piece with your fork.It is dense and soft.
You raise the fork to your lips…”

8. Motivation and Reward Learning
High
calorie
foods
Food cues
Thal
Ins
Dopamine:
– Medications that inhibit D2
receptors
(antipsychotics, e.g.
clozapine)
 appetite and  weight
gain
– Medications that blocks
reuptake of DA in presynaptic
neurons ( DA)
(psychostimulant, e.g.
methylphenidate)
 weight

9. Stress and Motivation
Threat,
Stress and
Metabolic
Hormones
Thal
Ins
 Stress hormones: Cortisol,
ACTH
 CRF: Critical brain stress
peptide
 Noradrenergic Signalls: NE
and EPI
 Dopamine: Motivation and
Adaptive Learning
 Serotonin: Regulation of
homeostatic states
 GABA/Glutamate:
Inhibitiona nd excitation

10. Page et al., JAMA, 2013
z = -8 z = -4 z = 0
Insula
Hyp
ACC
Caudate
Putamen
Thal-2
-6.6
T score
R L
R
T score
Thalamus
Putamen
CaudateHyp
NuAcc
6.51
2
z = -8 z = -3 z = 2
Functional Connectivity after Glucose
Ingestion (Hypothalamus seed)
Plasma Glucose (mg/dl)
HypothalamicCBF(ml/g/min)
r = -0.49, p<.04

11. Z= -6 Z= -2 Z= 2
prefrontal cortex
Caudate/puatmen
prefrontal cortex
putamen
InsulaInsula
Hyp
ACC
R L
Z= -6 Z= -2 Z= 2
Hypoglycemia (Hypo) compared to euglycemia
(Eu) increases wanting of HP foods and brain
response in craving, appetite and food reward
regions (shown in blue) and decreases activity in
prefrontal self control regions (in red) (p<.05
FWE corrected)
Page, Seo, de AguiarConstable, Sherwin, Sinha, JCI, 2011

12. Time
Picture Presentation
Rating
-Wanting Relax Before
Next Trial
6 secs 3 secs 3-9 secs
+
3 secs
Rating
-Liking
0 20 40 60 80 100 120
INSULIN (2mU/kg/min)
90
65
Time (min)
PlasmaGlucose(mg/dl)
Variable Rate Glucose Infusion
Visual Cues
Euglycemia
Visual Cues
Hypoglycemia
Eu Hypo Eu 1st Eu 2nd

13. striatum
Whole brain, voxel-based correlation analyses. Axial brain slices and corresponding scatter plots showing correlations between a) plasma
glucose levels and VMPFC/ACC response to high-calorie food images, b) plasma cortisol levels and left and right insula/striatal response to high-
calorie food images, p<0.01, two-tailed, FWE whole brain corrected. Areas in yellow indicate brain regions positively correlated to plasma glucose
and plasma cortisol levels. (ACC = anterior cingulate; VMPFC = ventromedial prefrontal cortex; L=left; R=right).
r = .56
r = .61 r = .60
ACC/VMPFC
Z = - 13 Z = 13
Z = - 6 Z = -2
insula striatum
Correlation between plasma glucose levels and prefrontal cortex/ACC activation
Correlation between plasma cortisol levels and bilateral insula/striatum activation
R L
R L
Page et al., JCI, 2011

14. Is Greater Understanding of the
Mechanisms Driving Excessive
Food Intake Opening New
Treatment Avenues?

15. Data in recovering cocaine dependent individuals; From Fox et al., 2012

16. Depression Scores Perceived Stress Scale
SBP – Systolic BP Food Craving Scores